Lipid A (endotoxin) is an essential component of the outer membranes of gram-negative bacteria. Genetic evidence has established that inhibition of its biosynthesis is lethal to gram-negative bacteria (Galloway, S. M.; Raetz, C. R. H. J. Biol. Chem. 1990, 265, 6394-6402; Kelly, T. M.; Stachula, S. A.; Raetz, C. R. H.; Anderson, M. S. J. Biol. Chem. 1993, 268, 19866-19874). Furthermore, blocking lipid A biosynthesis renders bacteria sensitive to other antibiotics which poorly penetrate gram-negative organisms with an intact outer membrane. The second step in lipid A biosynthesis involves the deacetylation of uridine diphosphate-3-0-R-3-hydroxymyristoyl!-N-acetylglucosamine by UDP-3-0-R-3-hydroxymyristoyl!-GlcNAc deacetylase. It is the object of this invention to describe inhibitors of this enzyme which have gram-negative antibacterial activity. Earlier attempts to block bacterial outer membrane biosynthesis at the ketodeoxyoctanoate (K.sub.do) stage met with limited success (Hammond, S. M.; et al. Nature 1987, 327, 730-732; Goldman, R.; Kohlbrenner, W.; Lartey, P.; Pernet, A. Nature 1987 329, 162-164.) since K.sub.do analogs penetrate bacteria poorly and inhibition at this step is not rapidly lethal to bacteria.
This invention is directed to certain heterocyclic hydroxamate compounds which have the ability to inhibit UDP-3-0-R-3-hydroxymyristoyl!-GlcNAc deacetylase and, thereby, have gram negative antibacterial activity. The compounds can be used to treat gram negative infections of man and of animals alone and in combination with other antibiotics.
It is a further object of this invention to describe procedures for the preparation of these compounds. Still further objects of this invention will be apparent from the specification.